The abuse of opioids has reached epidemic levels and has had devastating consequences in the past year. Deaths from opioid overdose have continued to increase and now exceed those from firearms, motor vehicle crashes, suicides and homicides. U.S. heroin availability has continued to increase as producers in Mexico rapidly increase production of low cost, high-purity white heroin (vs. the much less pure traditional black-tar heroin) in order to gain more of the market share. This is reflected in Mexican opium poppy cultivation that more than tripled between 2013-2016 reaching an estimated potential pure heroin production of 81 metric tons for 2016. The abuse of fentanyl and designer analogs is rapidly escalating and the most recent data indicate that these drugs were responsible for nearly 30,000 overdose fatalities annually exceeding those where heroin was the causative agent. We are currently pursuing three approaches to dealing with the opioid epidemic. The first is the ultimate development of a combination trivalent (or separate) anti-heroin, anti-HIV, antifentanyl vaccine(s). A successful combination vaccine of this type would suppress heroin and fentanyl abuse and protect against HIV infection from any route of exposure. Since injection drug use is a major factor in the transmission of HIV-1, suppression of the accompanying needle sharing would limit the spread of HIV and hepatitis in injection drug users. Such a vaccine should also be a valuable adjunct to prevent relapse in newly abstinent former narcotic abusers. This is an important consideration as the relapse rate for those able to quit is as high as 60% in the first year. Our second approach is the development of G-protein biased agonists as potential analgesics that lack the undesirable side effects of morphine (including respiratory depression, constipation and the development of tolerance and dependence). These drugs would replace the narcotic analgesics presently in use in the practice of medicine. The third approach in our triad is the design and chemical synthesis of combination mu/delta opioid receptor agonists. We have identified one such drug that does not show the respiratory depression produced by morphine in a rodent assay. Prior drug combination studies by others have shown that such compounds may lack the potentially fatal respiratory depression shown by morphine, fentanyl and congeners. We are continuing to prepare and evaluate experimental vaccines based on our novel approach of utilization of metabolically stable heroin-mimetic haptens. These haptens were covalently attached to the highly immunogenic tetanus toxoid (TT) with or without an HIV component and formulated with the Army Liposome Formulation. One such vaccine was derived from our lead heroin hapten 6-Amhap. The TT-6-AmHap vaccine significantly reduced heroin-induced antinociception and locomotion behavioral changes. We also examined the efficacy of the TT-6-AmHap vaccine in mice in the locomotion assay after a high-dose heroin challenge. We administered heroin at 50 mg/kg SC and found partial protection even at this dose of 50 times the ED50. Competition ELISA demonstrated that 6-AmHap-induced antibodies bound heroin and its metabolites, 6-acetylmorphine, morphine, and other abused opioids, including oxycodone, hydrocodone and hydromorphone. The antibodies did not cross-react with the therapies for substance abuse or the overdose rescue drug naloxone. The HIV portion of one of our vaccines related to TT-6-AmHap utilized a cyclic V2 (cV2) peptide previously identified as a correlate of prevention of acquisition of HIV in the RV144 phase III clinical trial. RV144 is the only HIV vaccine trial that has demonstrated efficacy to date. We immunized mice and sera were assessed for antibody titer to heroin and cV2. We assessed efficacy against heroin by subcutaneous heroin challenge. Antibody titers to cV2 were in the millions and bound to gp120 and gp70V1V2. The heroin-HIV vaccine induced protection against heroin challenge and afforded a very high titer cV2 antibodies, a proposed a correlate of efficacy in RV144. We conclude that an effective heroin-HIV vaccine is feasible based on our data. Our 6-amHap vaccine is on track to enter phase 1 clinical trials in 2020.